Human methylthioadenosine/adenosine depleting enzyme variants for cancer therapy
AssigneeBoard of Regents, The University of Texas System
InventorEverett Stone
Life of this patent
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Abstract
Disclosed herein are compositions related to conjugated polypeptides with MTA/ADO-degrading enzyme activity. The conjugated polypeptides are engineered to allow for maximal conjugation while maintaining catalytic activities. Also disclosed are nucleic acids, expression vectors, and host cells related to the conjugated polypeptides. Further disclosed are methods of using the pharmaceutical formulations comprising above to treat cancer.
Claims19
A method comprising administering to a subject a composition comprising polypeptides having methylthioadenosine-degrading activity,
- wherein said polypeptides have at least 90% sequence identity with the amino acid sequence of SEQ ID NO:
- 1,
- wherein each of at least a subset of said polypeptides is conjugated to at least two polymers,
- wherein said at least two polymers increase the serum half-life of conjugated said polypeptides compared to unconjugated said polypeptides,
- wherein said at least two polymers are not conjugated to any of said polypeptides at positions corresponding to both Lysine 225 and Lysine 238 of SEQ ID NO:
- 1,
- wherein the Kcat/Km of said subset of said polypeptides for degrading methylthioadenosine is at least 1×104 M−1s−1, and
- wherein said methylthioadenosine degrading activity is by phosphorolysis of methylthioadenosine into methylthioribose-phosphate and adenine.
A method of treating a subject with cancer comprising, administering to said subject an effective amount of a composition comprising polypeptides having methylthioadenosine phosphorylase activity,
- wherein said polypeptides have at least 90% sequence identity with the amino acid sequence of SEQ ID NO:
- 1,
- wherein each of at least a subset of said polypeptides is conjugated to at least two polymers,
- wherein said at least two polymers increase the serum half-life of conjugated said polypeptides compared to unconjugated said polypeptides,
- wherein said at least two polymers are not conjugated to any of said polypeptides at positions corresponding to both Lysine 225 and Lysine 238 of SEQ ID NO:
- 1,
- wherein said composition has a serum half-life of at least 36 hours and the Kcat/Km of said subset of said polypeptides for phosphorolysis of methylthioadenosine into methylthioribose-phosphate and adenine is at least 1×105 M−1s−1.
Dependencies are inferred from the claim text.